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Autosomal recessive retinal degenerative diseases cause visual impairment and blindness in both humans and dogs. Currently, no standard treatment is available, but pioneering gene therapy-based canine models have been instrumental for clinical trials in humans. To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs*1395), was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in the retina of an affected dog. The ABCA4 gene encodes a membrane transporter protein localized in the outer segments of rod and cone photoreceptors. In humans, the ABCA4 gene is associated with Stargardt disease (STGD), an autosomal recessive retinal degeneration leading to central visual impairment. A hallmark of STGD is the accumulation of lipofuscin deposits in the retinal pigment epithelium (RPE). The discovery of a canine homozygous ABCA4 loss-of-function mutation may advance the development of dog as a large animal model for human STGD.

The objective of the study was to examine whether a nutritional antioxidant supplementation could improve visual function in healthy dogs as measured by electroretinography (ERG) and autorefraction. A total of twelve Beagles, 6 to 8 years of age, with normal eyes upon indirect ophthalmoscopy and slit lamp biomicroscopy, were age and sex matched and randomly assigned to receive a feeding regimen for 6 months with or without a daily antioxidant supplementation. Portable, mini-Ganzfeld ERG and a Welch Allyn hand-held autorefractor were used to test retinal response and refractive error in the dogs at baseline and at the end of the supplementation period. All ERG a-wave amplitudes obtained were increased in the treatment group compared with those of dogs in the control group, with significant improvements in the scotopic high and photopic single flash cone ERG responses (P < 0·05 for both). For the b-wave amplitudes, all responses were similarly increased, with significant improvements in responses for the scotopic high light intensity stimulation (P < 0·05), and for photopic single flash cone and 30 Hz flicker (P < 0·01 for both) recordings. Change in refractive error was significantly less in the treatment group compared with that of the control group during the 6-month study (P < 0·05). Compared with the control group, the antioxidant-supplemented group showed improvement to varying degrees for retinal function and significantly less decline in refractive error. Dogs, like humans, experience retinal and lens functional decline with age. Antioxidant supplementation as demonstrated may be beneficial and effective in the long-term preservation and improvement of various functions of the canine eye.

Intensive breeding and selection on desired traits have produced high rates of inherited diseases in dogs. Hereditary retinal degeneration, often called progressive retinal atrophy (PRA), is prevalent in dogs with disease entities comparable to human retinitis pigmentosa (RP) and Leber’s congenital amaurosis (LCA). Recent molecular studies in the English Springer Spaniel (ESS) dog have shown that PRA cases are often homozygous for a mutation in the RPGRIP1 gene, the defect also causing human RP, LCA, and cone rod dystrophies. The present study characterizes the disease in a group of affected ESS in USA, using clinical, functional, and morphological studies. An objective evaluation of retinal function using electroretinography (ERG) is further performed in a masked fashion in a group of American ESS dogs, with the examiner masked to the genetic status of the dogs. Only 4 of 6 homozygous animals showed clinical signs of disease, emphasizing the need and importance for more precise studies on the clinical expression of molecular defects before utilizing animal models for translational research, such as when using stem cells for therapeutic intervention.

PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated (Pmel⁻/⁻). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel⁻/⁻ melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation.

The neuronal ceroid lipofuscinoses (NCLs) are devastating inherited progressive neurodegenerative diseases, with most forms having a childhood onset of clinical signs. The NCLs are characterized by progressive cognitive and motor decline, vision loss, seizures, respiratory and swallowing impairment, and ultimately premature death. Different forms of NCL result from mutations in at least 13 genes. The clinical signs of some forms overlap significantly, so genetic testing is the only way to definitively determine which form an individual patient suffers from. At present, an effective treatment is available for only one form of NCL. Evidence of NCL has been documented in over 20 canine breeds and in mixed-breed dogs. To date, 12 mutations in 8 different genes orthologous to the human NCL genes have been found to underlie NCL in a variety of dog breeds. A Dachshund model with a null mutation in one of these genes is being utilized to investigate potential therapeutic interventions, including enzyme replacement and gene therapies. Demonstration of the efficacy of enzyme replacement therapy in this model led to successful completion of human clinical trials of this treatment. Further research into the other canine NCLs, with in-depth characterization and understanding of the disease processes, will likely lead to the development of successful therapeutic interventions for additional forms of NCL, for both human patients and animals with these disorders.

Large mammals, including canids and felids, are affected by spontaneously occurring hereditary retinal diseases with similarities to those of humans. The large mammal models may be used for thorough clinical characterization of disease processes, understanding the effects of specific mutations, elucidation of disease mechanisms, and for development of therapeutic intervention. Two well-characterized feline models are addressed in this paper. The first model is the autosomal recessive, slowly progressive, late-onset, rod-cone degenerative disease caused by a mutation in the CEP290 gene. The second model addressed in this paper is the autosomal dominant early onset rod cone dysplasia, putatively caused by the mutation found in the CRX gene. Therapeutic trials have been performed mainly in the former type including stem cell therapy, retinal transplantation, and development of ocular prosthetics. Domestic cats, having large human-like eyes with comparable spontaneous retinal diseases, are also considered useful for gene replacement therapy, thus functioning as effective model systems for further research.